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Applies to insulin isophane: subcutaneous suspension

Cardiovascular

Other cardiovascular risk factors that are accentuated in persons with carbohydrate intolerance and hypertension include abnormalities in platelet function, clotting factors, the fibrinolytic system, and dyslipidemia. The relationship between diabetes, insulin, and these disorders is currently under investigation.

Cardiovascular side effects have included hyperinsulinemia. Given the high frequency of both microvascular and macrovascular diseases in patients with diabetes, some experts are evaluating insulin as a possible atherogenic agent. Controversy and continued study surround the role of hyperinsulinemia as the precursor of hypertension.[Ref]

Dermatologic

Dermatologic side effects have included lipohypertrophy (insulin is lipogenic) and lipoatrophy (probably immunologically-mediated). The incidence of lipoatrophy is markedly decreased with the use of purer forms of pork insulin or biosynthetic human insulin and when injection sites are alternated. Without proper hygiene, subcutaneous insulin injections may be complicated by infection.[Ref]

Endocrine

Endocrine side effects have included hypoglycemia, which has been the most common and serious side effect of insulin, occurring in approximately 16% of type 1 and 10% of type II diabetic patients (the incidence varies greatly depending on the populations studied, types of insulin therapy, etc). Although there are counterregulatory endocrinologic responses to hypoglycemia, some responses are decreased, inefficient, or absent in some patients. Severe hypoglycemia usually presents first as confusion, sweating, or tachycardia, and can result in coma, seizures, cardiac arrhythmias, neurological deficits, and death. Blood or urine glucose monitoring is recommended in patients who are at risk of hypoglycemia or who do not recognize the signs and symptoms of hypoglycemia. The risk for developing hypoglycemia is higher in patients receiving intensive or continuous infusion insulin therapy. The association between insulin and dyslipidemia is currently being evaluated.[Ref]

Permanent neuropsychological impairment has been associated with recurrent episodes of severe hypoglycemia.

In one retrospective study of 600 randomly selected patients with insulin-treated diabetes mellitus, the only reliable predictors of severe hypoglycemia were a history of hypoglycemia, a history of hypoglycemia-related injury or convulsion, and the duration of insulin therapy. Those with a history of hypoglycemia had been treated with insulin for 17.4 years, which was significantly longer than the 14.3 years in the insulin-treated patients without a history of hypoglycemia.

Human insulin does not appear to be associated with hypoglycemic episodes more often than animal insulin. Caution is recommended when switching from animal (either bovine or pork) to purified porcine insulin or biosynthetic human insulin, however, because of increased potency or bioavailability.[Ref]

Gastrointestinal

Gastrointestinal side effects have been rarely reported. GI distress tends to resolve with dose reduction.[Ref]

General

Intensive insulin therapy causes an increase in body fat as a result of the elimination of glycosuria and reduction in 24-hour energy expenditure. The reduction in 24-h energy expenditure is the result of an insulin-associated decrease in triglyceride/free fatty acid cycling and nonoxidative glucose and protein metabolism.[Ref]

General side effects have included weight gain, sometimes presenting as edema associated with abrupt restoration of glucose control in a patient whose control was previously poor. Weight gain may be due to more efficient use of calories during insulin therapy, suggesting additional benefits of dietary and exercise modifications. Patients on intensive insulin therapy may be more likely to experience weight gain.[Ref]

Hematologic

The effects of insulin-induced hypoglycemia on hemostasis may explain some of the clinical observations of embolic phenomenon during treatment of diabetic ketoacidosis.

Limited data show that diabetics have a significantly lower basal concentration of tissue plasminogen activator.[Ref]

Hematologic side have included an increase in the concentration of von Willebrand factor, due to insulin-induced hypoglycemia. Increased von Willebrand factor, combined with hypoglycemia-associated decreased plasma volume and increased plasma viscosity, may predispose patients to reduced peripheral perfusion or embolic phenomenon. A single case of insulin-induced hemolytic anemia has been reported.[Ref]

Hypersensitivity

Hypersensitivity side effects have included both local and systemic reactions. These reactions are becoming rare (less than 1% of patients) due to the use of purer forms of pork insulin or biosynthetic human insulin. Local reactions may present as erythema, swelling, heat, or subcutaneous nodules. They usually occur within the first two weeks of therapy, then disappear. True allergy to insulin is rare, and sensitization is usually associated with specific animal proteins in bovine and less pure forms of porcine insulins.[Ref]

A diabetic patient with true allergy to insulin can undergo desensitization. Desensitization kits and protocols are available from some insulin manufacturers.[Ref]

Immunologic

Immunologic analysis of anaphylaxis to some insulin preparations in some cases has revealed markedly elevated serum levels of lgE and lgG to protamine, but not to regular insulin.[Ref]

Immunologic side effects have included the formation of anti-insulin antibodies, particularly animal insulin formulations were used. The presence of these antibodies causes the elimination half-life of insulin to increase.[Ref]

Metabolic

Rare cases of hypophosphatemia have been associated with the use of glucose, insulin, and potassium infusions during the treatment of myocardial infarction.[Ref]

Metabolic side effects have included reports of hypokalemia and hypomagnesemia, particularly in patients treated for diabetic ketoacidosis (DKA). Insulin increases the intracellular transport of phosphate, which often results in hypophosphatemia during treatment of DKA.[Ref]

Ocular

Ocular side effects have included bilateral presbyopia (blurry vision) during the beginning of therapy. This is thought to be due to changes in the osmotic equilibrium between the lens and the ocular fluids, and is usually self-limited.[Ref]

Renal

Renal side effects have included significantly decreased renal plasma flow and glomerular filtration rate, and significantly increased urinary albumin excretion rate due to insulin-induced hypoglycemia. These changes were usually reversible upon resolution of hypoglycemia.[Ref]

Hypoglycemia is associated with increased plasma dopamine, epinephrine, and plasma renin activity. Acute changes in renal function during insulin-induced hypoglycemia, therefore, may result from direct stimulation of the efferent sympathetic nerves to the kidney and hormonal counterregulatory mechanisms.[Ref]

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